Beta thalassemia in Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G----C)

Data on the distribution of beta thalassemia among over 6,000 Melanesians reveals a major difference in the carrier rates between populations in the malarious coastal regions of New Guinea and those living in the historically malaria-free Highlands. The island of Maewo in Vanuatu has a particularly high incidence of beta + thalassemia associated with a single restriction enzyme haplotype. Direct cloning into a plasmid vector and sequence analysis demonstrate that the mutation is a G to C transversion at position 5 of intron 1 of the beta- globin gene. Oligonucleotide probe surveys indicate that this variant accounted for all cases of beta thalassemia studied from Maewo. It is also common in coastal Papua New Guinea where haplotype and oligonucleotide probe data suggest that the molecular basis of beta thalassmia is more heterogeneous.     

Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation

Activated protein C is a potent anticoagulant and profibrinolytic enzyme that can be derived from the vitamin-K-dependent serine protease zymogen, protein C, by the action of thrombin. Protein C antigen concentration was determined in plasmas from normals (n = 40) and from 38 patients with intravascular coagulation as evidenced by positive FDP (greater than micrograms/ml). Plasma protein C was 4 micrograms/ml in normals and was significantly depressed (less than 2 SD below the mean of normals) in 19 of the 38 patients. Of 15 patients with suspected intravascular coagulation but normal FDP, protein C was decreased in 5 individuals; 3 of these 5 patients had liver disease. Based on these results, we suggest that extensive activation of the coagulation system in vivo causes a significant consumption of protein C, presumably due to its activation by thrombin and subsequent clearance.     

Absence of a difference in the neurosecretory activity of supraoptic nucleus vasopressin neurons of neuroleptic-treated schizophrenic patients

Dysfunction in water intake and metabolism has frequently been reported in schizophrenia. The general population of schizophrenics under neuroleptic treatment secretes lower amounts of vasopressin than controls at comparable values of plasma osmolality. The purpose of the present study was to investigate the synthetic activity of vasopressin neurons of the dorsolateral supraoptic nucleus in schizophrenia on postmortem material using a battery of histochemical activity markers. Our material consisted of formalin-fixed and paraffin-embedded hypothalami from 5 schizophrenic patients under neuroleptic treatment and from 5 matched controls, obtained from The Netherlands' Brain Bank. DSM-III or DSM-IV criteria were used for the clinical diagnosis. The histochemical markers used to study the neuronal activity of the magnocellular vasopressin-synthesizing neurons were: cell size, size of the Golgi apparatus, and expression of vasopressin and tyrosine hydroxylase mRNA by in situ hybridization. Morphometric evaluation and statistical analysis (Mann-Whitney U test) were performed. Our results showed no statistically significant differences in any of the neuronal activity markers between schizophrenic patients and controls. Therefore, the neurosecretory activity of vasopressin neurons of the dorsolateral part of the supraoptic nucleus does not appear to be changed in schizophrenic patients under medication. Since our sample did not include patients with reported polydipsia or hyponatremia, prospective investigation is needed to evaluate the above-mentioned neuronal activity markers in such a particular subgroup of schizophrenic patients.     

Vasopressin and oxytocin neurons of the human supraoptic and paraventricular nucleus: size changes in relation to age and sex

The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei consist of arginine vasopressin (AVP)- and oxytocin (OT)-synthesizing neurons that send projections to the neurohypophysis, whereas the PVN also projects to other brain areas. A growing body of evidence in animals suggests the presence of sex differences in the vasopressinergic and oxytocinergic systems. The present study was aimed at determining whether the sizes of AVP and OT neurons in the human SON and PVN show sex differences, as earlier studies demonstrated that a change in neuronal size is a sensitive parameter for activity. The minimal and maximal diameters were determined to estimate the volumes of cell somata and cell nuclei in AVP and OT neurons stained with an antibody against human glycoprotein-(22-39), a part of the AVP precursor, and a monoclonal anti-OT antibody in 15 men and 17 women ranging in age from 29-94 yr. The AVP neurons appeared to be larger in young men than in young women (< or =50 yr old). In elderly women (>50 yr old) AVP cell size considerably exceeded that in young women. In elderly men AVP neurons were larger than in young men and elderly women, although these differences were not significant. In addition, AVP cell size correlated positively with age in women but not in men. No significant differences were found in the AVP cell nucleus volumes among all four groups studied. Sex differences in the size of the PVN vasopressin neurons were pronounced at the left side (P = 0.048) and absent at the right side (P = 0.368), indicating the presence of functional lateralization in this nucleus. No difference was found in any morphometric parameter of OT neurons in the PVN among the 4 groups studied. Thus, our data demonstrate sex differences in the size of the AVP neurons, and thus in their function, that are age and probably also side dependent and the absence of such changes in OT neurons in the PVN. These data provide a basis for the reported higher AVP plasma levels in men compared to women.     

Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients

Exposure to stress activates the hypothalamic–pituitary–adrenal (HPA) axis that stimulates glucocorticoid (GC) release from the adrenal. These hormones exert numerous effects in the body and brain and bind to a.o. glucocorticoid receptors (GR) expressed in the limbic system, including the hippocampus and amygdala. Hyperactivity of the HPA axis and disturbed stress feedback are common features in major depression. GR protein is present in the human hypothalamus and hippocampus, but little is known—neither in healthy subjects nor in depressed patients—about GR expression in the amygdala, a brain structure involved in fear and anxiety. Since chronic stress in rodents affects GR expression in the amygdala, altered GR protein level in depressed versus healthy controls can be expected. To test this, we investigated GR-α protein expression in the post-mortem human amygdala and assessed changes in ten major or bipolar depressed patients and eight non-depressed controls. Abundant GR immunoreactivity was observed in the human amygdala, both in neurons and astrocytes, with a similar pattern in its different anatomical subnuclei. In major depression, GR protein level as well as the percentage of GR-containing astrocytes was significantly higher than in bipolar depressed patients or in control subjects. Taken together, the prominent expression of GR protein in the human amygdala indicates that this region can form an important target for corticosteroids and stress, while the increased GR expression in major, but not bipolar, depression suggests possible involvement in the etiology of major depression.     

The human pineal gland and melatonin in aging and Alzheimer's disease

The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e. melatonin, are synchronized to the 24-hr day by environmental light, received by the retina and transmitted to the SCN via the retinohypothalamic tract. Melatonin not only plays an important role in the regulation of circadian rhythms, but also acts as antioxidant and neuroprotector that may be of importance in aging and Alzheimer's disease (AD). Circadian disorders, such as sleep-wake cycle disturbances, are associated with aging, and even more pronounced in AD. Many studies have reported disrupted melatonin production and rhythms in aging and in AD that, as we showed, are taking place as early as in the very first preclinical AD stages (neuropathological Braak stage I-II). Degeneration of the retina-SCN-pineal axis may underlie these changes. Our recent studies indicate that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the SCN is responsible for melatonin changes during the early AD stages. Reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation, to restore the circadian rhythm and to relieve the clinical circadian disturbances, has shown promising positive results.     

Myelinated and nonmyelinated nerves: comparison of proton MR properties

The magnetic resonance (MR) relaxation rates of protons were compared in the myelinated and nonmyelinated nerves of the garfish. The long, large olfactory nerve of the garfish, as an easily accessible source of nonmyelinated axons, is uniquely suited for such a comparison. The T1 and T2 measurements revealed distinct and consistent differences between nonmyelinated olfactory nerves and myelinated optic and oculomotor nerves. Comparisons between water content, lipid content, and relaxation rates indicated that the differences in MR properties represent complex differences in the distribution and physical environment of the constituent lipid and water protons.     

Comparison of β-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer’s disease patients: amorphic plaques and cytoskeletal changes occur independently

Alzheimer’s disease is characterized neuropathologically by senile plaques and cytoskeletal changes. It has been proposed that amorphic plaques would locally induce anterograde propagation of cytoskeletal changes in consecutive neurons followed by amorphic plaque deposition at their axonal terminals. The Alzheimer changes would spread in this way along neural pathways. To test the ‘primary amyloid anatomical cascade hypothesis’, Congo red staining, β-protein/A4 (Aβ) antiserum and Alz-50, which recognizes cytoskeletal changes, were applied to the hypothalamus and adjoining brain areas of five Alzheimer’s disease patients of 40–90 years of age and five age- and sex-matched controls. The results showed that (1) virtually all Aβ plaques in the hypothalamus were of the Congo red-negative amorphic type; (2) amorphic plaques and Alz-50-stained cytokeletal changes were observed not only in all Alzheimer’s disease patients but also in a non-demented, 90-year-old control subject; (3) the density of amorphic plaques in the hypothalamus was unrelated to the duration of the dementia; (4) the density of amorphic plaques was unrelated to that of Alz-50-stained cytoskeletal changes; (5) double-labeling with anti-Aβ and Alz-50 did not show an evident topical relationship between amorphic plaque deposition and the occurrence of cytoskeletal changes; and (6) the distribution of Aβ and Alz-50 staining in five brain areas, for which essential anatomical information is available, did not support the primary amyloid anatomical cascade hypothesis. Amorphic plaques and cytoskeletal changes rather occur independently. Received: 22 September 1997 / Revised, accepted: 9 January 1998     

Early sexual initiation: the role of peer norms

OBJECTIVE: To elucidate which components of peer norms influence the process of sexual initiation for young adolescents. Design. Prospective cohort study. Setting. Fourteen elementary and middle schools in an urban public school district. Participants. The 1389 sixth-grade students who completed the questionnaire at the beginning (time 1) and at the end (time 2) of the school year comprise the study sample. Mean age at time 1 was 11.7 years. RESULTS: Of students entering the sixth grade, 30% (n = 416) reported having already initiated sexual intercourse, 5% (n = 74) reported initiating sexual intercourse during the sixth-grade school year (initiated group), and 63% (n = 873) reported not having initiated sexual intercourse by the end of the sixth-grade school year (never group). Demographic comparisons revealed that students in the initiated group were significantly more likely than students in the never group to be older (11.9 years vs 11.6 years), male (58% vs 37%), African-American (70% vs 51%), attending a poorer school (87% vs 85%), and living in an area with a high proportion of single-parent families (45% vs 41%). Self-reports and reports of peers' participation in nonsexual risk behaviors were more common for students in the initiated group. Students in the initiated group were more likely than students in the never group to perceive: 1) a high prevalence of sexual initiation among peers; 2) social gains associated with early sexual intercourse; and 3) younger age of peers' sexual initiation. Students in the never group were more likely to believe that sexually-experienced 12-year-old boys would be negatively stigmatized compared with students in the initiated group. Three predictive models were developed to test the relationship between peer norms and the process of initiation. These models demonstrate that the strongest predictor of sexual initiation in sixth grade is having high intention to do so at the beginning of sixth grade. The strongest predictor of high intention is belief that most friends have already had sexual intercourse. Perceptions of social gain and stigma for sexually-experienced 12-year-old boys act independently of intention to decrease risk of early sexual initiation. CONCLUSION: Early sexual intercourse is not an unplanned experience for many teens. Decisions about initiation are strongly bound to social context with peers playing an important role in creating a sense of normative behavior. Specific components of peer norms impact the process of sexual initiation in both positive and negative ways. Interventions aimed at delaying the onset of sexual initiation need to focus on cohort norms as well as on an individual's perceptions and behaviors.